US9206154B2ActiveUtilityPatentIndex 39
Inverse agonists and neutral antagonists for the TSH receptor
Est. expiryApr 8, 2030(~3.8 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 35/04A61P 35/00A61P 5/14C07D 405/06A61K 31/517C07D 401/06C07D 239/91A61P 27/02
39
PatentIndex Score
0
Cited by
53
References
61
Claims
Abstract
TSHR inverse agonists and neutral antagonists that are useful for treating Graves' orbitopathy, Graves' hyperthyroidism and/or thyroid cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:
wherein R 1 is selected from a furanyl-containing group, a pyridinyl-containing group, a thienyl-containing group, hydroxyalkyl, or alkoxyalkyl;
R 2 is H, alkoxy, alkyl, substituted alkyl or halogen; and
R 3 -R 7 are each individually selected from H, alkyl, substituted alkyl, or aminocarbonyl, provided that at least one of R 3 or R 7 is not H; and
X is O or S; provided that the compound is not
2. The compound of claim 1 , wherein R 1 is selected from furan-2-ylmethyl, pyridin-3-ylmethyl, thien-2-ylmethyl or methoxyethyl.
3. The compound of claim 1 , wherein R 2 is methoxy.
4. The compound of claim 1 , wherein R 3 and R 7 are each methyl.
5. The compound of claim 1 , wherein X is O.
6. The compound of claim 1 , wherein X is S.
7. The compound of claim 1 , wherein R 5 is an aminocarbonyl group.
8. The compound of claim 1 , wherein the compound is:
9. The compound of claim 1 , wherein the compound is:
10. The compound of claim 1 , wherein the compound is:
11. The compound of claim 1 , wherein the compound is:
12. The compound of claim 1 , wherein the compound is:
13. A compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein R 1 is selected from a furanyl-containing group, a pyridinyl-containing group, a thienyl-containing group, hydroxyalkyl, or alkoxyalkyl;
R 2 is H, alkoxy, alkyl, substituted alkyl or halogen;
R 3 and R 7 are each individually alkyl;
R 4 -R 6 are each individually selected from H, alkyl, substituted alkyl, halogen, or aminocarbonyl; and
X is O or S; provided that the compound is not
14. The compound of claim 13 , wherein R 3 and R 7 are each methyl.
15. A compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein R 1 is selected from a furanyl-containing group, a pyridinyl-containing group, a thienyl-containing group, hydroxyalkyl, or alkoxyalkyl;
R 2 is H, alkoxy, alkyl, substituted alkyl or halogen;
R 3 , R 4 , R 6 and R 7 are each individually selected from H, alkyl, substituted alkyl, halogen, or aminocarbonyl, provided that at least one of R 3 or R 7 is not H;
R 5 is aminocarbonyl; and
X is O or S.
16. The compound of claim 2 , wherein R 3 and R 7 are each methyl.
17. The compound of claim 15 , wherein R 5 is acetamido.
18. A pharmaceutical composition comprising at least one pharmaceutically acceptable additive and a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein R 1 is selected from a furanyl-containing group, a pyridinyl-containing group, a thienyl-containing group, hydroxyalkyl, or alkoxyalkyl;
R 2 is H, alkoxy, alkyl, substituted alkyl or halogen; and
R 3 -R 7 are each individually selected from H, alkyl, substituted alkyl, halogen, or aminocarbonyl, provided that at least one of R 3 or R 7 is not H; and
X is O or S.
19. The pharmaceutical composition of claim 18 , wherein R 1 is selected is selected from furan-2-ylmethyl, pyridin-3-ylmethyl, thien-2-ylmethyl or methoxyethyl.
20. The pharmaceutical composition of claim 18 , R 3 and R 7 are each methyl.
21. A pharmaceutical composition comprising at least one pharmaceutically acceptable additive and a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:
wherein R 1 is selected from:
and
R 2 -R 6 are each individually selected from H, alkyl, substituted alkyl or halogen.
22. The pharmaceutical composition of claim 21 , wherein the compound is:
23. The pharmaceutical composition of claim 21 , wherein the compound is:
24. A method of treating Graves' disease in a subject, comprising administering to the subject an inverse agonist of TSHR or a neutral antagonist of TSHR.
25. The method of claim 24 , wherein the inverse agonist of TSHR or the neutral antagonist of TSHR comprises a 2,3-dihydroquinazolin-4-one compound.
26. A method of treating Graves' disease in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein R 1 is selected from a furanyl-containing group, a pyridinyl-containing group, a thienyl-containing group, hydroxyalkyl, or alkoxyalkyl;
R 2 is H, alkoxy, alkyl, substituted alkyl or halogen; and
R 3 -R 7 are each individually selected from H, alkyl, substituted alkyl, halogen, or aminocarbonyl; and
X is O or S.
27. The method of claim 24 , wherein the Graves' disease is Graves' orbitopathy.
28. The method of claim 24 , wherein the Graves' disease is Graves' hyperthyroidism.
29. The method of claim 28 , wherein the Graves' hyperthyroidism is recurrent Graves' hyperthyroidism following radioiodine or anti-thyroid treatment.
30. A method for inhibiting signaling stimulated by thyroid-stimulating antibodies (TSAbs) in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein R 1 is selected from a furanyl-containing group, a pyridinyl-containing group, a thienyl-containing group, hydroxyalkyl, or alkoxyalkyl;
R 2 is H, alkoxy, alkyl, substituted alkyl or halogen; and
R 3 -R 7 are each individually selected from H, alkyl, substituted alkyl, halogen, or aminocarbonyl; and
X is O or S.
31. The method of claim 30 , wherein the method comprises inhibiting stimulation of the thyroid-stimulating hormone receptor by TSAbs in thyroid or retro-orbital cells.
32. A method of treating hyperthyroidism in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein R 1 is selected from a furanyl-containing group, a pyridinyl-containing group, a thienyl-containing group, hydroxyalkyl, or alkoxyalkyl;
R 2 is H, alkoxy, alkyl, substituted alkyl or halogen; and
R 3 -R 7 are each individually selected from H, alkyl, substituted alkyl, halogen, or aminocarbonyl; and
X is O or S.
33. A method of treating thyroid cancer in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein R 1 is selected from a furanyl-containing group, a pyridinyl-containing group, a thienyl-containing group, hydroxyalkyl, or alkoxyalkyl;
R 2 is H, alkoxy, alkyl, substituted alkyl or halogen; and
R 3 -R 7 are each individually selected from H, alkyl, substituted alkyl, halogen, or aminocarbonyl, provided that at least one of R 3 or R 7 is not H; and
X is O or S.
34. The method of claim 33 , wherein the method comprises administering the compound subsequent to thyroid cancer surgery or radioactive iodine therapy.
35. The method of claim 33 , further comprising co-administering thyroid hormone therapy to the subject.
36. The method of claim 33 , wherein the thyroid cancer is recurrent or metastatic thyroid cancer.
37. The method of claim 33 , wherein administration of thyroid hormone is contraindicated in the subject.
38. The method of claim 36 , wherein the thyroid cancer is recurrent despite suppression of the subject's endogenous thyroid-stimulating hormone.
39. The method of claim 36 , wherein the thyroid cancer exhibits basal TSHR signaling activity and the compound inhibits such activity.
40. The method of claim 26 , wherein R 1 is selected from furan-2-ylmethyl, pyridin-3-ylmethyl, thien-2-ylmethyl or methoxyethyl.
41. The method of claim 26 , wherein R 2 is methoxy.
42. The method of claim 26 , wherein R 3 and R 7 are each methyl.
43. The method of claim 26 , wherein X is O.
44. The method of claim 26 , wherein X is S.
45. The method of claim 26 , R 5 is an aminocarbonyl group.
46. The method of claim 26 , wherein the compound is:
47. The method of claim 26 , wherein the compound is:
48. The method of claim 16 , wherein the compound is:
49. The method of claim 26 , wherein the compound is:
50. The method of claim 26 , wherein the compound is:
51. The method of claim 26 , wherein the compound is:
52. A method of treating thyroid cancer in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein R 1 is selected from:
and
R 2 -R 6 are each individually selected from H, alkyl, substituted alkyl or halogen.
53. The method of claim 52 , wherein the compound is:
54. The method of claim 52 , wherein the compound is:
55. A method of treating hyperthyroidism in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein R 1 is selected from:
and
R 2 -R 6 are each individually selected from H, alkyl, substituted alkyl or halogen.
56. The method of claim 55 , wherein the compound is:
57. The method of claim 55 , wherein the compound is:
58. A method of treating Graves' disease in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:
wherein R 1 is selected from:
and
R 2 -R 6 are each individually selected from H, alkyl, substituted alkyl or halogen.
59. The method of claim 27 , wherein the compound is:
60. The method of claim 27 , wherein R 1 is selected from furan-2-ylmethyl or pyridin-3-ylmethyl; R 2 is methoxy; and R 3 and R 7 are each methyl.
61. The method of claim 25 , wherein the 2,3-dihydroquinazolin-4-one compound is a 2-substituted, 3-substituted 2,3-dihydroquinazolin-4-one compound, wherein the substituent at the 2-position is a furanyl-containing group, a pyridinyl-containing group, a thienyl-containing group, hydroxyalkyl, or alkoxyalkyl, and the substituent at the 3-position is —Ar 1 —CH 2 —X—Ar 2 , wherein Ar 1 is a substituted or unsubstituted arylene group; Ar 2 is a substituted or unsubstituted aryl group; and X is O or S.Cited by (0)
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